This invention relates in general to a process for making medicinal pellets and in particular to a process for dispensing precise amounts of an active ingredient and carrier.
It has become widely acknowledged that standard oral and parenteral (intravenous or intramuscular) forms of drug delivery represent relatively inefficient means of administering therapeutic pharmaceuticals, due to considerable drawbacks associated with conventional drug-delivery methods. These drawbacks arise from the way in which standard dosage forms of pharmacologically active compounds are absorbed into the body, circulated through the blood stream, cleared and excreted. Conventional routes of administration generally require the administration of far more of a drug than is therapeutically warranted so that there will be adequate blood levels of drug between doses ("spiking"). Moreover, there are many therapeutically vital substances which present a narrow ratio of efficacy to toxicity that do not, therefore, lend themselves to traditional routes of administration. Additionally, drugs that require daily compliance with a multiple-dose regimen on the part of the patient pose a major problem in the management of the chronically ill, elderly, those with emotional disorders, and people whose lifestyles do not comfortably accommodate regular routine. The lists of conditions requiring such regimens is extensive and includes: diabetes; psychiatric diseases; cancer; and coronary artery disease, to name only a few.
In recent years, various types of novel sustained release drug-delivery systems have begun to receive widespread attention. Such drug-delivery systems include certain implantable devices which slowly dissolve or somehow release drugs while under the patient's skin. Implants are particularly effective and economical forms of treatment because a single administration of such a product can deliver, over a long period of time (a year or more), adequate therapeutic serum levels of a drug without reliance on patient compliance, frequent clinic visits and while avoiding over medication due to "spiking".
Of the known implantable drug delivery systems, bioabsorbable implants are preferred because such implants do not require surgical removal when the drug is depleted. Bioabsorbable implants can be made by various methods and utilizing various materials. Several methods have been practiced with steroid drugs. For example, a bioabsorbable implant can be made by tightly compressing a combination of a nonactive biocompatible binder and the steroid into a pellet. Such a pellet releases steroid more slowly and more uniformly than a pellet containing only pure steroid. The rate of release and the uniformity of release depend both on the precise relative amounts of the steroid and binder and on the homogeneity of the mixture prior to compression.
An important improvement over the compression process for making pellets, which results in even longer and more constant dissolution rates, is a method of melting a drug together with a sufficient amount of a nonactive lipoid carrier resulting, when cooled, in a "fused" pellet. Such fused pellets are capable of delivering microgram quantities of drug daily for a year or more. It is important that these pellets contain a homogeneous mixture of active ingredient and carrier in precise relative amounts to insure predictable and desirable release kinetics. This is particularly true where drugs such as steroids are being delivered because anything but a precise dosage could be ineffective or even harmful to the patient.
Fused pellets have proven unsuitable for a variety of reasons, largely related to the manufacturing processes used which are not easily reproducible. The background of such fused implants is discussed in greater detail in U.S. Pat. No. 4,244,949 (Gupta).
The methods suggested by Gupta and others for making such a fused implant rely heavily upon manual skills and do not lend themselves to automated mass production techniques. In particular, the best of the prior art methods requires pre-measuring and dispensing into very small vessels precise, minute amounts of active ingredient and carrier. Pre-measuring and dispensing of the ingredients by hand into the vessels introduces the potential for error and contamination. Moreover, this practice may necessitate an undesirable degree of human exposure to certain drugs in powder form, demanding the strictest controls according to the rules promulgated by the FDA. There currently are no acceptable substitutes for hand dispensing because it is believed that standard pharmaceutical dispensing machinery does not dispense the very small quantities of powder required for making such fused pellets with sufficient accuracy. This is especially true when the active ingredient comprises over 50% of the total pellet volume.
This invention overcomes these and other shortcomings. A process is provided for dispensing starting materials and forming a pellet that does not require the human manipulation and judgment previously enumerated and that is capable of automation and suitable for large-scale commercial production.
A particular object of the invention is to provide a process for dispensing an intimate mixture of starting materials in precise relative amounts and in an automated fashion where the active ingredient comprises over 50% of the final drug product.